Jordan V Craig
Medical Sciences, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA.
J Clin Oncol. 2008 Jun 20;26(18):3073-82. doi: 10.1200/JCO.2008.17.5190. Epub 2008 Jun 2.
During the first David A. Karnofsky Award lecture entitled "Thoughts on Chemical Therapy" in 1970, Sir Alexander Haddow commented about the dramatic regressions observed with estrogen in some breast cancers in postmenopausal women, but regrettably the mechanism was unknown. He was concerned that a cancer-specific target would remain elusive, without tests to predict response to therapy. At that time, I was conducting research for my PhD on an obscure group of estrogen derivatives called nonsteroidal antiestrogens. Antiestrogens had failed to fulfill their promise as postcoital contraceptives and were unlikely to be developed further by the pharmaceutical industry. In 1972, that perspective started to change and ICI 46,474 was subsequently reinvented as the first targeted therapy for breast cancer. The scientific strategy of targeting the estrogen receptor (ER) in the tumor, treating patients with long-term adjuvant therapy, examining active metabolites, and considering chemoprevention all translated through clinical trials to clinical practice during the next 35 years. Hundreds of thousands of women now have enhanced survivorship after their diagnosis of ER-positive breast cancer. However, it was the recognition of selective ER modulation (SERM) that created a new dimension in therapeutics. Nonsteroidal antiestrogens selectively turn on or turn off estrogen target tissues throughout the body. Patient care was immediately affected by the recognition in the laboratory that tamoxifen would potentially increase the growth of endometrial cancer during long-term adjuvant therapy. At that time, a failed breast cancer drug, keoxifene, was found to maintain bone density of rats (estrogenic action) while simultaneously preventing mammary carcinogenesis (antiestrogenic action). Perhaps a SERM used to prevent osteoporosis could simultaneously prevent breast cancer? Keoxifene was renamed raloxifene and became the first SERM for the treatment and prevention of osteoporosis as well as the prevention of breast cancer, but without an increase in endometrial cancer. There the story might have ended had the study of antihormone resistance not revealed a vulnerability of cancer cells that could be exploited in the clinic. The evolution of antihormone resistance over years of therapy reconfigures the survival mechanism of the breast cancer cell, so estrogen no longer is a survival signal but a death signal. Remarkably, remaining tumor tissue is again responsive to continuing antihormone therapy. This new discovery is currently being evaluated in clinical trials but it also solves the mystery mechanism of chemical therapy with estrogen noted by Haddow in the first Karnofsky lecture.
1970年，在首届以“化学疗法之思考”为题的大卫·A·卡诺夫斯基奖讲座上，亚历山大·哈多爵士评论了绝经后女性某些乳腺癌中雌激素所观察到的显著消退情况，但遗憾的是其机制尚不清楚。他担心在没有预测治疗反应的检测方法的情况下，癌症特异性靶点仍将难以捉摸。当时，我正在攻读博士学位，研究一组名为非甾体抗雌激素的 obscure 雌激素衍生物。抗雌激素作为性交后避孕药未能兑现其承诺，制药行业也不太可能进一步开发它。1972年，这种情况开始改变，ICI 46,474随后被重新开发为第一种乳腺癌靶向治疗药物。在接下来的35年里，针对肿瘤中的雌激素受体（ER）、用长期辅助治疗对患者进行治疗、研究活性代谢物以及考虑化学预防等科学策略都通过临床试验转化为了临床实践。现在，数十万女性在被诊断为ER阳性乳腺癌后生存率得到了提高。然而，选择性雌激素受体调节剂（SERM）的发现为治疗学开创了一个新领域。非甾体抗雌激素能选择性地开启或关闭全身的雌激素靶组织。实验室发现他莫昔芬在长期辅助治疗期间可能会增加子宫内膜癌的生长，这一发现立即影响了患者护理。当时，一种失败的乳腺癌药物凯昔芬被发现能维持大鼠的骨密度（雌激素作用），同时预防乳腺癌发生（抗雌激素作用）。也许一种用于预防骨质疏松症的SERM可以同时预防乳腺癌？凯昔芬被重新命名为雷洛昔芬，成为第一种用于治疗和预防骨质疏松症以及预防乳腺癌且不会增加子宫内膜癌风险 的SERM，但如果没有抗激素耐药性研究揭示出癌细胞在临床上可被利用的弱点，这个故事可能就到此为止了。多年治疗中抗激素耐药性的演变重新配置了乳腺癌细胞的生存机制，因此雌激素不再是生存信号而是死亡信号。值得注意的是，残留的肿瘤组织再次对持续的抗激素治疗有反应。这一新发现目前正在临床试验中进行评估，但它也解开了哈多在首届卡诺夫斯基讲座中提到的雌激素化学疗法的神秘机制之谜。
